The availability of 18 large Utah kindreds with hereditary hemochromatosis provides an opportunity 1) to establish the mode of inheritance of the disease, 2) to describe the phenotypic expression of the disease in heterozygotes and homozygotes, 3) to establish appropriate diagnostic criteria for the disease, 4) to define the relationship of the hemochromatosis gene to "secondary" non-transfusional hemochromatosis such as occurs in a few patients with hemolytic anemia, sideroblastic anemia, porphyria cutanea tarda and beta-Thalassemia minor, and 5) to study the metabolic defect in the regulation of iron uptake. We have now studied 450 individuals in 18 pedigrees. The disease is inherited in an autosomal recessive fashion. The gene is in close proximity to the HLA locus on chromosome six. We estimate a gene frequency in the Utah population of 5.6%. This calculates to a disease frequency of 0.3% and a heterozygote frequency of 10.6%. Increased saturation of transferrin is the earliest detectable laboratory abnormality in homozygotes and permits identification of a portion of heterozygotes. Iron uptake in normal and hemochromatotic cells is not regulated at the point of transferrin binding to the transferrin receptor. The site of the regulation of iron uptake and the defect in hemochromatosis remain to be determined.